| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Mantle Cell Lymphoma
|
| Linfoma Mantellare |
|
| E.1.1.1 | Medical condition in easily understood language |
Mantle Cell Lymphoma
|
| Linfoma Mantellare |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10026798 |
| E.1.2 | Term | Mantle cell lymphomas |
| E.1.2 | System Organ Class | 100000004851 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of acalabrutinib (ACP-196) in combination with bendamustine and rituximab (BR) compared with placebo in combination with BR based on Independent Review Committee (IRC) assessment of progression-free survival (PFS) per the Lugano Classification for Non Hodgkin Lymphoma (NHL) (Cheson 2014) in subjects with previously untreated mantle cell lymphoma (MCL). |
| Valutare l’efficacia di acalabrutinib in combinazione con bendamustina e rituximab (BR) rispetto al placebo più BR sulla base della valutazione del Comitato di revisione indipendente (IRC) della sopravvivenza libera da progressione (PFS) secondo la classificazione di Lugano del linfoma non Hodgkin (NHL) (Cheson 2014; Appendice 14) — di seguito indicata come Classificazione di Lugano per NHL — in soggetti affetti da linfoma mantellare (MCL) non precedentemente trattati |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate acalabrutinib (ACP-196) in combination with BR compared with placebo in combination with BR in terms of:
• Investigator-assessed PFS per the Lugano Classification for NHL
• Investigator-assessed ORR per the Lugano Classification for NHL
• IRC-assessed overall response rate (ORR), defined as a subject achieving either a partial response (PR) or complete response (CR) per the Lugano Classification for NHL.
• Overall survival (OS)
• IRC-assessed duration of response (DOR) per the Lugano Classification for NHL
• IRC-assessed time to response (TTR) per the Lugano Classification for NHL
• IRC-assessed ORR (CR + PR) per Revised Response Criteria for Malignant Lymphoma (Cheson 2007)
• PRO by Functional Assessment of Cancer Therapy Lymphoma (FACT-Lym) scale score
• PRO by the EuroQol (EQ-5D-5L) index score
• PRO by the EORTC QLQ-C30 score
• Medical Ressource utilization (MRU) |
Valutare acalabrutinib in combinazione con BR rispetto al placebo più BR in termini di:
•PFS valutata dallo sperimentatore secondo la Classificazione di Lugano per NHL
•Tasso di risposta globale valutato dallo sperimentatore (ORR; risposta completa [CR] + risposta parziale [PR]) secondo la Classificazione di Lugano per NHL
•ORR valutata dall’IRC (CR + PR) secondo la Classificazione di Lugano per NHL
•Sopravvivenza complessiva (OS)
•Durata della risposta valutata dall’IRC (DOR) secondo la Classificazione di Lugano per NHL
•Tempo alla risposta valutato dall’IRC (TTR) secondo la Classificazione di Lugano per NHL
•ORR valutata dall’IRC (CR + PR) secondo i Revised Response Criteria for Malignant Lymphoma (Cheson 2007)
•Esito riferito dal paziente (PRO) mediante il punteggio secondo la scala Functional Assessment of Cancer TherapyLymphoma (FACT-Lym)
•PRO mediante il punteggio dell’indice EuroQol (EQ-5D-5L)
•PRO mediante punteggio del Quality of Life Quest Core 30 (EORTC)
-Uso risorse mediche |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Other types of substudies
Specify title, date and version of each substudy with relative objectives: - Pharmacokinetic Sub-study
Due to a short half-life, trough concentrations of acalabrutinib are generally not measurable. Intensive PK samples will be collected for acalabrutinib, bendamustine and bendamustine metabolite from approximately 40 subjects in the PK substudy predose/before the start of the bendamustine infusion and postdose/after the start of infusion.
- Biomarker Evaluation
Peripheral blood mononuclear cells (PBMC) and tumor samples will be used for biomarker evaluations. To determine the temporal effect of study drugs on the phenotype of malignant cells in subjects, blood samples will be collected and analyzed centrally per the Schedule of Assessments.
|
Altre tipologie di sottostudi
specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: - Sottostudio di Farmacocinetica
Due to a short half-life, trough concentrations of acalabrutinib are generally not measurable. Intensive PK samples will be collected for acalabrutinib, bendamustine and bendamustine metabolite from approximately 40 subjects in the PK substudy predose/before the start of the bendamustine infusion and postdose/after the start of infusion.
- Valutazione dei Biomarker
Peripheral blood mononuclear cells (PBMC) and tumor samples will be used for biomarker evaluations. To determine the temporal effect of study drugs on the phenotype of malignant cells in subjects, blood samples will be collected and analyzed centrally per the Schedule of Assessments.
|
|
| E.3 | Principal inclusion criteria |
1. Men and women, = 65 years of age.
2. Pathologically confirmed MCL, with documentation of monoclonal CD20+ B cells that have a chromosome translocation t(11;14)(q13;q32) and/or overexpress cyclin D1 in association with other relevant markers(CD5, CD19,CD20, PAX5)
3. MCL requiring treatment and for which no prior systemic anticancer therapies have been received.
4. Presence of radiologically measurable lymphadenopathy and/or extranodal lymphoid malignancy (as defined by Lugano Classification for NHL).
5. ECOG performance status of = 2.
6. Men who are sexually active and can beget children must agree to use highly effective forms of contraception during the study and for 6 months after the last dose of bendamustine, or 12 months after the last dose of rituximab, whichever is longest. Highly effective forms of contraception are defined in Section 9.2.2.
7. Men must agree to refrain from sperm donation during the study and for 6 months after the last dose of bendamustine, or 12 months after the last dose of rituximab, whichever is longest.
8. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty.
9. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local patient privacy regulations). |
1. Uomini e donne di età = a 65 anni.
2. MCL patologicamente confermato, con documentazione di cellule B CD20+ monoclonali che hanno una traslocazione cromosomica t(11;14)(q13;q32) e/o iperespressione della ciclina D1 in associazione con altri markers rilevanti(CD5, CD19,CD20, PAX5).
3. MCL che richiede trattamento e per il quale non sono state ricevute precedenti terapie antitumorali sistemiche.
4. Presenza di linfoadenopatia e/o neoplasia linfoide extranodale radiologicamente misurabile (come definito dalla Classificazione di Lugano per NHL).
5. Stato di performance Eastern Cooperative Oncology Group (ECOG) = 2.
6. Gli uomini che sono sessualmente attivi e in grado di generare devono accettare di utilizzare forme altamente efficaci di contraccezione durante lo studio e per 6 mesi dopo l’ultima dose di bendamustina o 12 mesi dopo l’ultima dose di rituximab, a seconda di quale sia il periodo più lungo. Le forme altamente efficaci di contraccezione sono definite nella Sezione 9.2.2.
7. Gli uomini devono accettare di non donare sperma durante lo studio e per 6 mesi dopo l’ultima dose di bendamustina o 12 mesi dopo l’ultima dose di rituximab, a seconda di quale sia il periodo più lungo.
8. Disposti e in grado di partecipare a tutte le valutazioni e le procedure richieste in questo protocollo di studio, compresa la deglutizione di capsule senza difficoltà.
9. Capacità di comprendere lo scopo e i rischi dello studio e fornire un consenso informato firmato e datato e l’autorizzazione ad utilizzare le informazioni sanitarie protette (in conformità alle normative nazionali e locali sulla privacy dei pazienti). |
|
| E.4 | Principal exclusion criteria |
| .1.History of prior malignancy except: a.Malignancy treated with curative intent and with no evidence of active disease present for more than 2 years before screening and felt to be at low risk for recurrence by treating physician. b.Adequately treated lentigo maligna melanoma without current evidence of disease or adequately controlled nonmelanomatous skin cancer. c.Adequately treated carcinoma in situ without current evidence of disease. 2.Subjects for whom the goal of therapy is tumor debulking before stem cell transplant. 3.History of CNS lymphoma or leptomeningeal disease.4.Uncontrolled AIHA or ITP. 5.Major surgical procedure within 28 days before first dose of study drug. 6.Significant cardiovascular disease such as uncontrolled or untreated symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of first dose of study drug, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or QTc >480 msec (Friderica’s formula: QT/RR0.33) at screening.7.ANC <1.0x109/L or platelet count<75x109/L; for subjects with disease involvement in the bone marrow, ANC <0.75x109/L or platelet count<50x109/L. Subjects will only be considered eligible if peripheral blood counts can be maintained independent of growth factors or transfusions during the screening period. 8.Total bilirubin>1.5xULN; or AST or ALT>2.5xULN. 9.Estimated creatinine clearance of <50mL/min, formula of Cockcroft and Gault 10.Prothrombin time/INR or aPTT (in the absence of a Lupus anticoagulant) >2.0xULN. r.11.Malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of the stomach, extensive small bowel resection that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass. 12.Uncontrolled active systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment), or intravenous anti infective treatment within 2 weeks before first dose of study drug. 13.Known history of infection with HIV. 14.Ongoing immunosuppressive therapy, including systemic (eg, IV or oral) corticosteroids within 2 weeks before the first dose of study drug. 15.Known history of anaphylaxis or hypersensitivity to bendamustine, rituximab, or any of their components. 16.Serologic status reflecting active hepatitis B or C infection. a.Subjects who are anti-HBc positive and who are surface antigen negative will need to have a negative PCR result before randomization. Those who are HbsAg positive or hepatitis B PCR positive will be excluded. b.Subjects who are hepatitis C antibody positive will need to have a negative PCR result before randomization. Those who are hepatitis C PCR positive will be excluded.17.Received a live virus vaccination within 28 days of first dose of study drug.18.History of stroke or intracranial hemorrhage within 6 months of first dose of study drug.19.History of bleeding diathesis. 20.Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before first dose of study drug.21.Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists within 7 days of first dose of study drug.22.Requires treatment with a strong CYP3A inhibitor/inducer.23.Requires treatment with proton pump inhibitors. Subjects receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment to this study.24.Concurrent participation in another therapeutic clinical trial. |
| 1.Anamnesi di neoplasia precedente, eccezione: a.Neoplasia trattata con intento curativo e senza evidenza di malattia presente attiva per oltre 2 anni prima dello screening e ritenuto a basso rischio di recidiva dal medico curante. b.Lentigo maligno adeguatamente trattato senza evidenza di malattia o cancro della pelle non melanomatoso adeguatamente controllato.c.Carcinoma in situ adeguatamente trattato senza evidenza di malattia attiva. 2.Soggetti per i quali l’obiettivo della terapia è la citoriduzione tumorale prima del trapianto di cellule staminali. 3.Qualsiasi storia di linfoma del sistema nervoso centrale (SNC) o malattia leptomeningea. 4.Anemia emolitica autoimmune (AIHA) o porpora trombocitopenica idiopatica (ITP) non controllate. 5.Procedura chirurgica maggiore entro 28 giorni prima della prima dose del farmaco in studio.6.Malattia cardiovascolare significativa, come aritmie incontrollate o sintomatiche, insuffic.cardiaca congestizia o infarto miocardico entro 6 mesi dalla prima dose del farmaco in studio, o qualsiasi malattia cardiaca di classe 3 o 4 come definito dalla New York Heart Association Functional Classification, o intervallo QT corretto (QTc)>480 msec (calcolato usando la formula di Friderica: QT/RR0.33) allo screening. 7.Conta assoluta dei neutrofili (ANC) <1,0x109/L o conta piastrinica <75x109/L; per soggetti con coinvolgimento della malattia nel midollo osseo, ANC<0,75x109/L o conta piastrinica<50x109/L. I soggetti saranno considerati idonei solo se le conte del sangue periferico possono essere mantenute indipendentemente dai fattori di crescita o da trasfusioni durante il periodo di screening. 8.Bilirubina totale>1,5x ULN; o AST o ALT>2,5xULN.9.Clearance stimata della creatinina<50ml/min, calcolata utilizzando la formula di Cockcroft e Gault 10.Tempo di protrombina/rapporto internazionale normalizzato (INR) o tempo di tromboplastina parziale attivata (aPTT, in assenza di lupus anticoagulante) >2,0xULN. 11.Sindrome da malassorbimento, resezione dello stomaco, resezione dell’intestino tenue estesa che rischia di influenzare l’assorbimento, malattia infiammatoria intestinale sintomatica, ostruzione intestinale parziale o completa o restrizioni gastriche e chirurgia bariatrica, come ad esempio bypass gastrico.12.Infezione fungina, batterica, virale o altro tipo di infezione sistemica attiva (definita come presenza di segni/sintomi legati alle infezioni e senza miglioramento, nonostante antibiotici appropriati o altro trattamento), o trattamento anti infettivo endovenoso entro 2 settimane prima della prima dose del farmaco in studio.13.Storia nota di infezione da virus HIV.14.Terapia immunosoppressiva in corso, inclusi corticosteroidi sistemici entro 2 settimane dalla prima dose del farmaco in studio. 15.Storia nota di anafilassi o ipersensibilità a bendamustina, rituximab o uno dei loro componenti. 16.Stato sierologico che riflette un’infezione da epatite B o C attiva. a.I soggetti positivi all’anticorpo core dell’epatite B (anti-HBc) o negativi all’antigene di superficie dovranno avere un risultato negativo alla PCR prima della randomizzazione. b.soggetti positivi all’anticorpo epatite C dovranno avere un risultato negativo alla PCR prima della randomizzazione. 17.ricevuto una vaccinazione con virus vivo entro 28 giorni dalla prima dose del farmaco in studio. 18.Storia di ictus o emorragia intracranica entro 6 mesi dalla prima dose del farmaco.19. Storia di diatesi emorragica.20Presenza ulcera gastrointestinale diagnosticata con endoscopia entro 3 mesi dalla prima dose del farmaco21.Pazienti che necessitano o ricevono anticoagulazione con warfarin antagonisti della vitamina K equivalenti entro 7 giorni dalla prima dose del farmaco.22.Paz. che necessitano di un trattamento con un forte inibitore/induttore del citocromo P450 3A (CYP3A) 23.Paz. che necessitano di trattamento con inibitori della pompa protonica.24.Partecipazione concomitante in un’altra sperimentazione clinica terapeutica. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint of the study is PFS as assessed by IRC per the
Lugano Classification for NHL.
The primary analysis is a comparison of PFS between Arm 1
(acalabrutinib plus BR) and Arm 2 (placebo plus BR). |
| L’endpoint primario dello studio è la PFS come valutato dall’IRC secondo la Classificazione di Lugano per NHL. L’analisi primaria è un confronto di PFS tra il Braccio 1 (acalabrutinib più BR) e il Braccio 2 (placebo più BR). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Response assessments will be based on the Lugano Classification for NHL, which incorporates assessments via PET/CT and CT alone. During treatment, CT scans will be performed for tumor assessments at Week 12 (± 7 days), then every 12 weeks until Week 96 (± 7 days), and then every 24 weeks (± 7 days) thereafter. |
| Response assessments will be based on the Lugano Classification for NHL, which incorporates assessments via PET/CT and CT alone. During treatment, CT scans will be performed for tumor assessments at Week 12 (± 7 days), then every 12 weeks until Week 96 (± 7 days), and then every 24 weeks (± 7 days) thereafter. |
|
| E.5.2 | Secondary end point(s) |
•Investigator-assessed PFS per the Lugano Classification for NHL
•Investigator-assessed ORR (CR+PR) per the Lugano Classification for NHL
•IRC-assessed ORR (CR+PR) per the Lugano Classification for NHL
•OS
•IRC-assessed DOR per the Lugano Classification for NHL
•IRC assessed TTR per the Lugano Classification for NHL
•IRC-assessed ORR (CR + PR) per Revised Response Criteria for Malignant Lymphoma (Cheson 2007)
•PRO as measured by change in scores from baseline to each assessment using the FACT-Lym scale
•PRO as measured by change in scores from baseline to each assessment using the EQ-5D-5L index score
•PRO by change in scores from baseline to each assessment using the EORTC QLQ-C30 score
•MRU associated with the therapy, including the number of hospitalizations, emergency department visits, blood product transfusions, and use of hematopoietic growth factors. |
• PFS valutata dallo sperimentatore secondo la Classificazione di Lugano per NHL
• ORR valutata dallo sperimentatore (CR + PR) secondo la Classificazione di Lugano per NHL
• ORR valutata dall’IRC (CR + PR) secondo la Classificazione di Lugano per NHL
• OS
• DOR valutata dall’IRC secondo la Classificazione di Lugano per NHL
• TTR valutato dall’IRC secondo la Classificazione di Lugano per NHL
• ORR valutata dall’IRC (CR + PR) secondo i Revised Response Criteria for Malignant Lymphoma (Cheson 2007).
• PRO misurata utilizzando la scala FACT-Lym.
• PRO misurata utilizzando il punteggio dell’indice EQ-5D-5L.
• PRO misurata utilizzando il punteggio EORTC QLQ-C30.
• MRU associato alla terapia, compreso il numero di ricoveri, visite al pronto soccorso, trasfusioni di emoderivati e uso di fattori di crescita ematopoietici. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Response assessments will be based on the Lugano Classification for NHL, which incorporates assessments via PET/CT and CT alone. During treatment: CT scans will be performed for tumor assessments at Week 12 (± 7 days), then every 12 weeks until Week 96 (± 7 days), and then every 24 weeks (± 7 days) thereafter. PET/CT scans will be performed at Weeks 12 and 24 (± 7 days), and then only to confirm CR thereafter. Subjects with confirmed CR are not required to undergo further PET/CT scans on study unless there is suspicion of disease progression PRO assessment will be performed at screening, on Day 1 of Cycles 3, 5, and 8, then every 4 cycles until discontinuation of study treatment, and then every 12 weeks thereafter until disease progression or use of alternative anticancer therapy. |
| Response assessments will be based on the Lugano Classification for NHL, which incorporates assessments via PET/CT and CT alone. During treatment: CT scans will be performed for tumor assessments at Week 12 (± 7 days), then every 12 weeks until Week 96 (± 7 days), and then every 24 weeks (± 7 days) thereafter. PET/CT scans will be performed at Weeks 12 and 24 (± 7 days), and then only to confirm CR thereafter. Subjects with confirmed CR are not required to undergo further PET/CT scans on study unless there is suspicion of disease progression PRO assessment will be performed at screening, on Day 1 of Cycles 3, 5, and 8, then every 4 cycles until discontinuation of study treatment, and then every 12 weeks thereafter until disease progression or use of alternative anticancer therapy. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 77 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Brazil |
| Canada |
| Hong Kong |
| Israel |
| Korea, Republic of |
| Mexico |
| New Zealand |
| Peru |
| Russian Federation |
| Taiwan |
| Ukraine |
| United States |
| Vietnam |
| Belgium |
| Czechia |
| France |
| Germany |
| Greece |
| Hungary |
| Italy |
| Poland |
| Romania |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
